Continuous Monitoring Versus Intermittent Auscultation of Wheezes in Patients Presenting With Acute Respiratory Distress.

BACKGROUND: Auscultation for an extended period of time using a wearable stethoscope enables objective computerized analysis and longitudinal assessment of lung sounds. However, this auscultation method differs from bedside auscultation in that clinicians are not present to optimize the quality of auscultation. No prior studies have compared these two auscultation methods. OBJECTIVE: The aim of this study was to compare intermittent auscultation using a conventional stethoscope with continuous auscultation using a wearable stethoscope for wheeze detection in patients who present with acute respiratory distress. METHODS: Patients presenting to the emergency department with acute respiratory distress were enrolled. The Strados Remote Electronic Stethoscope Platform (RESP™) was used for continuous auscultation, and intermittent auscultation was performed using a U.S. Food and Drug Administration-cleared electronic stethoscope. A recording was made with an electronic stethoscope. Subsequently, continuous recording was made using RESP™, which continued until the patient was admitted or discharged from the emergency department. The number of captured wheezes in each recording was counted and validated by two board-certified physicians. RESULTS: From May 2018 to May 2019, 43 patients were enrolled in the study. Three patients were excluded from analysis due to incomplete audio recording data. The mean length of recording was 62.3 min for continuous auscultation and 0.7 min for intermittent auscultation; 77.5% (31 of 40) of intermittent recordings contained wheezes, in contrast to 85% (34 of 40) of continuous recordings. CONCLUSIONS: Extending the duration of auscultation using a wearable stethoscope in a noisy clinical environment showed comparable performance to standard of care intermittent auscultation in identifying patients who have wheezes.

A first-in-human phase 0 clinical study of RNA interference-based spherical nucleic acids in patients with recurrent glioblastoma.

Glioblastoma (GBM) is one of the most difficult cancers to effectively treat, in part because of the lack of precision therapies and limited therapeutic access to intracranial tumor sites due to the presence of the blood-brain and blood-tumor barriers. We have developed a precision medicine approach for GBM treatment that involves the use of brain-penetrant RNA interference-based spherical nucleic acids (SNAs), which consist of gold nanoparticle cores covalently conjugated with radially oriented and densely packed small interfering RNA (siRNA) oligonucleotides. On the basis of previous preclinical evaluation, we conducted toxicology and toxicokinetic studies in nonhuman primates and a single-arm, open-label phase 0 first-in-human trial (NCT03020017) to determine safety, pharmacokinetics, intratumoral accumulation and gene-suppressive activity of systemically administered SNAs carrying siRNA specific for the GBM oncogene Bcl2Like12 (Bcl2L12). Patients with recurrent GBM were treated with intravenous administration of siBcl2L12-SNAs (drug moniker: NU-0129), at a dose corresponding to 1/50th of the no-observed-adverse-event level, followed by tumor resection. Safety assessment revealed no grade 4 or 5 treatment-related toxicities. Inductively coupled plasma mass spectrometry, x-ray fluorescence microscopy, and silver staining of resected GBM tissue demonstrated that intravenously administered SNAs reached patient tumors, with gold enrichment observed in the tumor-associated endothelium, macrophages, and tumor cells. NU-0129 uptake into glioma cells correlated with a reduction in tumor-associated Bcl2L12 protein expression, as indicated by comparison of matched primary tumor and NU-0129-treated recurrent tumor. Our results establish SNA nanoconjugates as a potential brain-penetrant precision medicine approach for the systemic treatment of GBM.

Effects of AGI-1067 and probucol after percutaneous coronary interventions.

BACKGROUND: AGI-1067, a metabolically stable modification of probucol, is an equipotent antioxidant to probucol but is pharmacologically distinct. In a multicenter trial, we studied whether AGI-1067 reduces restenosis assessed by intravascular ultrasound (IVUS) after percutaneous coronary intervention (PCI) compared with placebo and probucol used as a positive control. METHODS AND RESULTS: Two weeks before PCI, 305 patients were randomly assigned to 1 of 5 treatment groups: placebo, probucol 500 mg BID, or AGI-1067 70, 140, or 280 mg once daily. Patients were treated for 2 weeks before and 4 weeks after PCI. Baseline and 6-month follow-up IVUS were interpreted by a blinded core laboratory. Stents were used in 85% of patients. Luminal area at the PCI site at follow-up was 2.66+/-1.58 mm2 for placebo, 3.69+/-2.69 mm2 for probucol, 2.75+/-1.76 mm2 for AGI-1067 70 mg, 3.17+/-2.26 mm2 for AGI-1067 140 mg, and 3.36+/-2.12 mm2 for AGI-1067 280 mg (P=0.02 for the dose-response relationship; P< or =0.05 for AGI-1067 280 mg and probucol versus placebo). There was a mean narrowing of 5.3 mm3 of reference segment lumen in the placebo group and an enlargement in the AGI-1067 140- and 280-mg groups at follow-up (P=0.05 for 140 mg). An increase in QTc interval >60 ms occurred in 4.8% of placebo patients, 17.4% of probucol patients, and 4.8%, 2.4%, and 2.5% of patients in the AGI-1067 groups (P=0.02). CONCLUSIONS: AGI-1067 and probucol reduce restenosis after PCI. In contrast to probucol, AGI-1067 did not cause prolongation of the QTc interval and improved lumen dimensions of reference segments, suggestive of a direct effect on atherosclerosis.